Background: Chronic hepatitis B virus carriers receiving chemotherapy develop a high hepatitis B virus reactivation rate (38-53%) with a high mortality (37-60%). Few studies have characterized the efficacy of lamivudine in the treatment of chemotherapy-induced hepatitis B virus reactivation. Aim: To determine whether lamivudine prophylaxis reduces chemotherapy-induced hepatitis B virus reactivation and mortality. Methods: The medical records of all hepatitis B surface antigen-positive patients with malignancy treated with chemotherapy since 1995 at the National University Hospital of Singapore were identified, and divided into those who received lamivudine prophylaxis before chemotherapy (P) and those who did not (NP). The parameters examined included gender, age, malignancy type, steroid usage, number of chemotherapy courses and regimens, follow-up duration and hepatitis B virus status. The outcome measures were hepatitis B virus reactivation (abrupt rise of serum alanine aminotransferase to > 200 IU/L) and reactivation death. Patients with primary hepatoma or liver metastasis were excluded. Results: Thirty-five patients were identified: 16 in the P group and 19 in the NP group. The baseline characteristics of the two groups were similar. Seven of the 19 patients in the NP group and none of the 16 patients in the P group developed reactivation (36.8% vs. 0%, P = 0.009). Six of the seven patients in the NP group who developed reactivation received lamivudine at that time, but five died (mortality, 71.4%), whilst no patient in the P group died from reactivation (P = 0.064). Conclusions: Prophylactic lamivudine appears to prevent hepatitis B virus reactivation and its associated mortality in patients treated with chemotherapy. This should be confirmed with prospective studies.